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Vitamin D controls T cell antigen receptor signaling and activation of human T cells.

Author(s): Niels Ødum, Peter Schjerling, Marina Rode von Essen, Klaus Olgaard, Carsten Geisler, Martin Kongsbak

Publication date: 2010-03-31

Keywords: Cells, Cultured, Enzyme Activation, immunology, Humans, Immunoblotting, In Situ Hybridization, Lymphocyte Activation, Phospholipase C gamma, biosynthesis, Receptors, Antigen, T-Cell, Receptors, Calcitriol, Signal Transduction, Vitamin D

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Abstract

Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-gamma1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering led to an upregulation of approximately 75-fold in PLC-gamma1 expression, which correlated with greater TCR responsiveness. Induction of PLC-gamma1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-gamma1, which are required for subsequent classical TCR signaling and T cell activation.

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TCR down-regulation controls virus-specific CD8+ T cell responses.

Charlotte Bonefeld, Mariëlle Haks, Bodil Nielsen … (2008)

The CD3gamma di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3gamma di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8(+) T cells is impaired in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8(+) T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3gamma-mediated TCR down-regulation in virus-specific CD8(+) T cell responses.